Flavoring of drug-containing chewing gums

ABSTRACT

A chewing gum comprising at least one active pharmaceutical ingredient (API) with a core onto which is applied at least one inner polymer film coating and thereafter onto which is applied at least one outer hard coating. A preferred API is nicotine. Flavoring agents may be incorporated in the core, in the at least one inner polymer film coating and/or in the at least one outer hard coating. The gums formed exhibit a long lasting effect of flavoring agent(s) and result in the domination of flavoring agents in the coating(s) over flavoring agent(s) in the core, thereby (a) avoiding problems of chemical or pharmaceutical incompatibility between an API in the core and flavoring agent(s) in the coating(s) and (b) achieving an increased control of the release of the API and of non-active excipients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Pat. application Ser. No.11/131,561, filed May 18, 2005, the entirety of which is herebyincorporated by reference as if fully set forth herein.

FIELD OF THE INVENTION

This invention relates to improved drug-containing gums, especiallythose containing nicotine.

BACKGROUND OF THE INVENTION

The present invention is useful for any active pharmaceutical ingredient(API), which may be administered with a chewing gum. A preferred API isnicotine. The following background mainly concerns nicotine as the API.

Tobacco dependence and reduction thereof is an important field. Inrecent years, with the recognition of the harmful effects of tobaccosmoking, there have been numerous campaigns and programs by governmentalagencies and various health groups and other interested organisations todisseminate information about the adverse health effects resulting fromtobacco smoking. Moreover, and as a result of this recognition of theharmful effects, there have been many programs directed to attempts inreducing smoking incidence.

Nicotine is an organic compound and is the principal alkaloid oftobacco. Nicotine is the chief addictive ingredient in the tobacco usedin cigarettes, cigars, snuff and the like. Nicotine is also an addictivedrug, though, and smokers characteristically display a strong tendencyto relapse after having successfully stopped smoking for a time.Nicotine is the worlds second most used drug, after caffeine from coffeeand tea.

The main problem with tobacco smoking is its enormous implications onhealth. It is estimated that smoking related diseases cause some 3-4million deaths per year. According to Centers for Disease Control andPrevention. Cigarette smoking among adults—United States, 1995, MMWR1997; 46:1217-1220, around 500,000 persons in the USA die each year as aresult of tobacco use. In fact, excessive smoking is now recognised asone of the major health problems throughout the world. This grimconsequence of tobacco smoking has urged many medical associations andhealth authorities to take very strong actions against the use oftobacco.

Even though tobacco smoking is decreasing in many developed countriestoday it is hard to see how the societies could get rid of the world'ssecond most used drug.

The most advantageous thing a heavy smoker can do is to reduce orpreferably even stop smoking completely. Experience shows, however, thatmost smokers find this extremely difficult since, mostly, tobaccosmoking results in a dependence disorder or craving. The WHO has in itsInternational Classification of Disorders a diagnosis called TobaccoDependence. Others like the American Psychiatric Association call theaddiction Nicotine Dependence. It is generally accepted that thesedifficulties to stop smoking result from the fact those heavy smokersare dependent on nicotine. The most important risk factors are, however,substances that are formed during the combustion of tobacco, such ascarbon monoxide, tar products, aldehydes, and hydrocyanic acid.

The effects of nicotine must be considered. The administration ofnicotine can give satisfaction and the usual method is by smoking,either by smoking e.g. a cigarette, a cigar or a pipe. However, smokinghas health hazards and it is therefore desirable to formulate analternative way of administering nicotine in a pleasurable manner thatcan be used to facilitate withdrawal from smoking and/or used as areplacement for smoking.

When smoking a cigarette, nicotine is quickly absorbed into the smoker'sblood and reaches the brain within around ten seconds after inhalation.The quick uptake of nicotine gives the consumer a rapid satisfaction orkick. The satisfaction, then, lasts during the smoking time of thecigarette and for a period of time thereafter. The poisonous, toxic,carcinogenic, and addictive nature of smoking has provided efforts formethods, compositions and devices, which help in breaking the habit ofsmoking cigarettes.

Nicotine is an addictive poisonous alkaloid C₅H₄C₄H₇NCH₃, derived fromthe tobacco plant. Nicotine is also used as an insecticide.Approximately 40 milligrams of nicotine is able to kill an adult (MerckIndex).

Nicotine replacement products are important in the reduction of smoking.One way to reduce smoking is to provide nicotine in a form or mannerother than by smoking and some products have been developed to fulfillthis need. Nicotine containing formulations are currently the dominatingtreatments for tobacco dependence.

The successes in achieving reduction in the incidence of smoking havebeen relatively poor using presently known products. The present stateof the art involves both behavioral approaches and pharmacologicalapproaches. More than 80% of the tobacco smokers who initially quitsmoking after using some behavioral or pharmacological ap proach. Thesepersons who singly reduce smoking incidence generally relapse and returnto the habit of smoking at their former rate of smoking within about aone year's period of time.

As an aid for those who are willing to stop smoking there are severalways and forms of nicotine replacement products available on the market;such as nicotine chewing gum. Several methods and means have beendescribed for diminishing the desire of a subject to use tobacco, whichcomprises the step of administering to the subject nicotine or aderivative thereof as described in e.g., U.S. Pat. No. 5,810,018 (oralnicotine spray), U.S. Pat. No. 5,939,100 (nicotine containingmicrospheres) and U.S. Pat. No. 4,967,773 (nicotine containing lozenge).

Nicotine-containing nose drops have been reported (Russell et al.,British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., Brit.J. of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, aredifficult to administer and are not convenient for use at work or inother public situations. Ways of administrating nicotine by way ofdelivering nicotine directly into the nasal cavity by spraying is knownfrom U.S. Pat. No. 4,579,858; DE 32 41 437; and WO 93/127 64. There may,however, be local nasal irritation with use of nasal nicotineformulations. The difficulty in administration also results inunpredictability of the dose of nicotine administered.

The use of skin patches for transdermal administration of nicotine hasbeen reported (Rose, in Pharmacologic Treatment of Tobacco Dependence,(1986) pp. 158-166, Harvard Univ. Press). Nicotine-containing skinpatches that are in wide use today can cause local irritation and theabsorption of nicotine is slow and affected by cutaneous blood flow.

Also, inhaling devices resembling a cigarette are known for uptake ofnicotine vapours as suggested in U.S. Pat. No. 5,167,242. Said means andmethods address the problems associated with addiction to nicotine.

Nicotine chewing gum is an important approach. One of the mostsuccessful approaches to date in reducing the incidence of smokingrelies upon nicotine containing chewing gum that is designed to reducesmoking withdrawal symptoms. The reported success rate is approximatelytwice that of placebo.

Various approaches have been discussed for smoking reduction and/orcessation. One successful product that is used as a smoking substituteand/or as a smoking cessation aid and which is based on nicotine is thechewing gum Nicorette®. This product was one of the first nicotinereplacement forms that was approved by the Food and Drug Administration(FDA) and is still one of the most used nicotine replacement products.Nicorette® chewing gum has been on the market in many countries forseveral years. In this chewing gum the nicotine is present in the formof a complex with an insoluble cation-exchanger (polacrilex) that isdispersed in a gum base. The nicotine is slowly released from the gumdue to chewing and will reach similar plasma levels as when smoking acigarette after about 30 minutes depending on the chewing technique,i.e., slow or active. Patents related to this product are, e.g., U.S.Pat. Nos. 3,877,468; 3,901,248; and 3,845,217.

WO 98/23165 discloses a chewing gum wherein nicotine may be in thecoating. This concept may provide rapid release of the nicotine from thecoated chewing gum, but not a sufficiently rapid buccal uptake of thenicotine. The fraction of the released nicotine that is not immediatelyabsorbed will be flushed down in the gastrointestinal (G.I.) tract bythe saliva, thereby possibly causing hiccups and other G.I. sideeffects. Once absorbed by the G.I. route, this swallowed nicotine willbe subjected to first pass metabolism.

WO 00/13662 discloses a chewing gum for systemic, oral administration ofan active whereby said active is administered by the chewing gumcomposition in a bi-phasic manner. The bi-phasic delivery is obtained bythe gum matrix as such, not from any coating.

WO 00/19977 discloses a substantially moisture-free and possibly coatedchewing gum for delivery of an active. The possible coating is notdescribed as being buffered.

U.S. Pat. No. 5,433,960, assigned to William Wrigley Jr. Company,discloses a stick-shaped chewing gum being coated with an edible film,which comprises at least one active chewing gum agent such as sweetener,flavor, softener, slip agent, flavor enhancer, antioxidant and/or color.The coating may comprise a first layer as an edible film and a secondlayer comprising e.g. wax, fat, oil and/or a lipid derivative. It is notdisclosed that the stick-shaped chewing gum with its coating maycomprise any other drug than said active chewing gum agent.

WO 02/102357, assigned to Pharmacia AB, discloses a nicotine-containingchewing gum product comprising at least one coating, which coating isbuffered.

U.S. Pat. No. 5,135,761, assigned to the Wrigley Company, discloses acoated chewing gum comprising a center, an emulsifier coating coveringthe center, and a hard panned coating covering the emulsifier coating.The emulsifier coating does not contain a polymer.

EP 302024A, assigned to Warner-Lambert, discloses a chewing gumcomprising a first portion containing an L-aspartic acid derivedsweetener, a second portion containing at least one flavoring agent, anda protective barrier film between the first and the second portions.

U.S. Pat. No. 4,828,845, assigned to Warner-Lambert, discloses a processfor producing a coated chewing gum, whereby at least three coatingsolutions are applied one after the other by spraying on to a chewinggum core.

ZA 8702849, assigned to Warner-Lambert, discloses a chewing gum with acore and at least two coating solutions, both solutions comprisingsorbitol and film-forming agents, such as hydroxypropylmethyl cellulose(“HPMC”).

U.S. Pat. No. 4,933,190, assigned to Warner-Lambert, discloses a chewinggum capable of releasing increased amounts of sweetness, which has afirst inner coating comprising polyvinyl acetate and a second outercoating comprising a hydrophilic polymer.

None of the above references disclose any solution to the combinedproblems of obtaining a long lasting effect of flavoring agent(s),domination of flavoring agents in the coating(s) over flavoring agent(s)in the core, avoiding problems of chemical or pharmaceuticalincompatibility between a drug in the core and flavoring agent(s) in thecoating(s), and/or increasing the control of the release of the drug.

SUMMARY OF THE INVENTION

This invention relates to drug-containing chewing gums, comprising a gumcore over which is applied at least one inner polymer film coating andwhereon is applied at least one outer hard coating over the innerpolymer film coating. Flavoring agents may be incorporated in the core,in the at least one inner polymer film coating and/or in the at leastone outer hard coating. A preferred drug is nicotine. Advantages of theinvention include long lasting effect of flavoring agent(s), dominationof flavoring agents in the coating(s) over flavoring agent(s) in thecore, the avoidance of problems of chemical or pharmaceuticalincompatibility between a drug in the core and flavoring agent(s) in thecoating(s), and increased control of the release of the drug and ofnon-active excipients.

The present invention also provides, as particular embodiments, new andimproved products as a coated chewing gum containing an activepharmaceutical ingredient (API) and providing for obtaining of a longlasting effect of flavoring agent(s), domination of flavoring agents inthe coating(s) over flavoring agent(s) in the core, avoiding problems ofchemical or pharmaceutical incompatibility between an API in the coreand flavoring agent(s) in the coating(s), and/or increasing the controlof the release of the drug.

A preferred API is nicotine in any form.

DETAILED DESCRIPTION OF THE INVENTION

With reference to this invention, the term “chewing gum” means allchewable gum products. The term “API” intends to mean activepharmaceutical ingredient. The term “nicotine” intends to mean nicotinein any form, be it the free base form, a salt, a complex or any otherform.

For flavored API-containing chewing gums the invention provides asolution to the combined problem of obtaining a long lasting effect ofthe flavoring agent(s), obtaining domination of flavoring agents in thecoating(s) over flavoring agent(s) in the core, avoiding problems ofchemical or pharmaceutical incompatibility between an API in the coreand flavoring agent(s) in the coating(s), and/or increasing the controlof the release of the drug. Known techniques for flavoring chewing gumsimply that flavoring agents are added to a gum core and optionally to ahard coating on the core. Anyhow, such flavoring does not solve thepreceding problem.

According to the present invention said combined problem is solved byproviding a chewing gum core with at least one inner polymer filmcoating and at least one outer hard coating, whereby the flavoringagent(s) is/are added to at least the inner polymer film coating. TheAPI may be in the core and/or in one or more of the coatings. For anicotinecontaining chewing gum the nicotine is preferably in the coreand in an at least one inner polymer film coating for providing quicknicotine release from the film and slow nicotine release from the core.For a dextromethorphan-containing chewing gum the dextromethorphan ispreferably only in an at least one inner polymer film coating to avoidentrapment of dextromethorphan in the core and for quick release fromthe film.

The API may be any API suitable for delivery with a chewing gum. Themost preferred API is nicotine. Other suitable APIs are preferablyselected among the below listed compounds.

Teeth whitening actives may be included in one or both coatings of thepresent invention. The actives suitable for whitening are selected fromthe group consisting of oxalates, peroxides, metal chlorites,perforates, percarbonates, peroxyacids, and mixtures thereof. Suitableperoxide compounds include hydrogen peroxide, calcium peroxide, sodiumperoxide, carbamide peroxide, urea peroxide, sodium percarbonate andmixtures thereof. Optionally, the peroxide is hydrogen peroxide.Suitable metal chlorites include calcium chlorite, barium chlorite,magnesium chlorite, lithium chlorite, sodium chlorite and potassiumchlorite. Additional whitening actives may be hypochlorite and chlorinedioxide. A preferred chlorite is sodium chlorite. The effectiveness ofwhitening actives can, optionally, be enhanced by means of a catalyst,i.e. a two-component peroxidecatalyst system. Useful whitening agentcatalysts or catalytic agents can be found in U.S. Pat. No. 6,440,396 toMcLaughlin, herein incorporated by reference in its entirety as to thedescription of whitening agents and systems.

When incorporating peroxide actives, the coating compositions of thepresent invention can, optionally, contain peroxide active stabilizers.Peroxide active stabilizers suitable for use herein include, but are notlimited to, polyethylene glycols such as PEG 40 or PEG 600; zinc saltssuch as zinc citrate; polyoxyalkylene block-polymers (e.g. Pluronics);aminocarboxylic acids or salts thereof; glycerols; dyes such as Blue #1or Green #3; phosphates such as phosphoric acid, sodium phosphate orsodium acid pyrophosphate; stannous salts such as stannous chloride;sodium stannate; citric acid; etidronic acid; carbomers orcarboxypolymethylenes such as those of the Carbopol® series, butylatedhydroxytoluene (BHT), ethylenediaminetetraacetic acid (EDTA) andmixtures thereof.

Anti-tartar agents useful herein include phosphates. Phosphates includepyrophosphates, polyphosphates, polyphosphonates and mixtures thereof.Pyrophosphates are among the best known phosphates for use in dentalcare products. Pyrophosphate ions delivered to the teeth derive frompyrophosphate salts. The pyrophosphate salts useful in the presentcompositions include the dialkali metal pyrophosphate salts,tetra-alkali metal pyrophosphate salts, and mixtures thereof. Disodiumdihydrogen pyrophosphate (Na₂H₂P₂O₇), tetrasodium pyrophosphate(Na₄P₂O₇), and tetrapotassium pyrophosphate (K₄P₂O₇) in theirnon-hydrated as well as hydrated forms are preferred. Anticalculusphosphates include potassium and sodium pyrophosphates; sodiumtripolyphosphate; diphosphonates, such asethane-1-hydroxy-1,1-diphosphonate; 1-azacycloheptane-1,1-diphosphonate;and linear alkyl diphosphonates; linear carboxylic acids and sodium andzinc citrate.

Agents that may be used in place of or in combination with the abovepyrophosphate salt include materials such as synthetic anionic polymersincluding polyacrylates and copolymers of maleic anhydride or acid andmethyl vinyl ether, e.g. Gantrez, as described, for example, in U.S.Pat. No. 4,627,977, to Gaffar et al. herein incorporated by reference inits entirety as to the description of such agents, as well as e.g.polyamino propane sulfonic acid (AMPS), zinc citrate trihydrate,polyphosphates, e.g. tripolyphosphate and hexametaphosphate,diphosphonates, e.g. EHDP and AMP, polypeptides, such as polyasparticand polyglutamic acids, and mixtures thereof.

Antimicrobial agents can also be present in the coating compositions ofthe present invention as oral agents and/or systemic actives. Suchagents may include, but are not limited to,5-chloro-2-(2,4-dichlorophenoxy)-phenol, commonly referred to astriclosan, chlorhexidine, alexidine, hexetidine, sanguinarine,benzalkonium chloride, salicylamide, domiphen bromide, cetylpyridiumchloride (CPC), tetradecyl pyridinium chloride (TPC);N-tetradecyl-4-ethyl pyridinium chloride (TDEPC); octenidine;delmopinol, octapinol, and other piperidino derivatives, niacinpreparations; zinc/stannous ion agents; antibiotics such as AUGMENTIN,amoxycillin, tetracycline, doxycyline, minocycline, and metronidazole;and analogs, derivatives and salts of the above antimicrobial agents andmixtures thereof.

Anti-inflammatory agents can also be present in the coating compositionsof the present invention as oral agents and/or systemic actives. Suchagents may include, but are not limited to, non-steroidalanti-inflammatory agents or NSAIDs, such as propionic acid derivatives;acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylicacid derivatives; and oxicams. All of these NSAIDs are fully describedin U.S. Pat. No. 4,985,459 to Sunshine et al., incorporated by referenceherein in its entirety as to the description of such NSAIDs. Examples ofuseful NSAIDs include acetylsalicylic acid, ibuprofen, naproxen,benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen,indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, microprofen,tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,bucloxic acid and mixtures thereof. Also useful are the steroidalanti-inflammatory drugs such as hydrocortisone and the like, and COX-2inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib,etoricoxib or mixtures thereof. Mixtures of any of the aboveanti-inflammatories may be used.

Other materials that can be used with the present invention includecommonly known mouth and throat products. These products include, butare not limited to, upper respiratory agents such as phenylephrine,diphenhydramine, dextromethorphan, bromhexine and chlorpheniramine,gastrointestinal agents such as famotidine, loperamide and simethicone,anti-fungals such as miconazole nitrate, antibiotics and analgesics suchas ketoprofen and fluribuprofen.

At least the inner polymer coating comprises a flavoring agent. Also theouter hard coating may comprise a flavoring agent.

One or more of the coatings may comprise sweetening agents and/orfurther additives as described below.

One particular embodiment comprises embedding the flavoring agent in thepolymer coating to prolong the flavoring sensation.

In order to reduce manufacturing costs and in order to facilitateproduct approval for similar chewing gums by health authorities it isoften desirable to use the same core with differently flavored coatings.Thereby the flavor of the core needs to be dominated by the flavor ofthe coating(s). This effect is obtained by the present invention wherethe flavor of the at least one inner polymer coating may dominate overthe flavor of the core. An example of such domination is when a fruitflavor in the at least one inner polymer coating dominates over a mintflavor of the core. The mechanism behind this flavor domination is thatthe flavor in the polymer coating has a slow release therefrom. Further,upon chewing, part of the polymer coating gets embedded in the core,from where the polymer film flavor is subsequently slowly released.Polymer coating also allows for addition of a large percentage of flavoras compared to a hard coating.

An outer hard coating may cover the polymer film coating whereby anobjectionable taste of an API or of another excipient in the polymerfilm coating which directly affects the oral mucosa is avoided.

By keeping the flavoring agent in the polymer coating, and optionallyalso in the hard coating, the flavoring agent is held isolated from anAPI in the core, thus avoiding the possible problem of chemical orpharmaceutical incompatibility between the API and the flavoring agent.An example of such incompatibility is nicotine in direct contact withcinnamon flavor, whereby cinnamon aldehydes in the cinnamon flavordegrade the nicotine.

Polymers suitable for use in the at least one inner polymer coating arepreferably selected from, but not limited to, the group consisting ofhydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinylalcohol, sodium alginate, polyethylene glycol, pullulan, tragacanth gum,guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylatecopolymer, carboxyvinyl polymer, amylose, high amylose starch,hydroxypropylated high amylose starch, dextrin, pectin, chitin,chitosan, gelatin, zein, gluten, soy protein isolate, wheyprotein-isolate, casein and mixtures thereof. Suitable polymers alsoinclude water-insoluble polymers selected from the group consisting ofhydrogenated vegetable oils, hydrogenated caster oil, polyvinylchloride, shellac, polyurethane, cellulose derivatives, gum rosins, woodrosens, waxes, acrylate and methacrylate polymers, copolymers of acrylicand methacrylic acid esters and mixtures thereof.

The amount of gum base in the coated chewing gum according to theinvention is about 15-80% by weight of the total gum core, andpreferably at least about 40% by weight. The amount of gum base employedfor the most desirable slow release of nicotine is usually in the higherranges when nicotine is employed per se or when an absorbed form isused.

The gum base may be of any conventional nature known in the art. Forexample it may comprise a gum base of natural or synthetic originreadily available from a commercial source. Natural gum bases includee.g. chicle, jelutong-, lechi de caspi-, soh-, siak-, katiau-, sorwa-,balata-, pendare-, malaya-, and peach gums, natural cautchouc andnatural resins such as dammar and mastix. Synthetic gum bases are amixture of:

-   -   elastomers (polymers, masticating substances),    -   plasticizer (resin, elastomers, solvent, hydrophobic resin),    -   filler (texturizer, water-insoluble adjuvant),    -   softener (fat),    -   emulsifier,    -   wax,    -   antioxidant, and    -   anti-tacking agents (vinyl polymer, hydrophilic resin).        Other examples of gum bases are gums including agar, alginate,        arabic gum, carob gum, carrageenan, ghatti gum, guar gum, karaya        gum, pectin, tragacanth gum, locust beam gum, gellan gum and        xanthan gum.

Examples of gelling agents comprise gum arabic, starch, gelatine, agar,and pectin.

When nicotine in any form is incorporated in the chewing gum mass inaccordance with the present invention, it is possible to employ a widevariety of chewing gum compositions and amounts of the chewing gum base.Different chewing gum products may be composed depending on theconsumer's preference and the purpose of use, in respect of the nicotinelevel, nicotine distribution and other additives.

According to one aspect of the invention, the chewing gum may comprisenicotine in any form. The nicotine may act as a stimulant to e.g. obtaina rapid reduction of the urge to smoke or to use tobacco. Moreparticularly, the nicotine should be in a saliva soluble form tofacilitate the release of the agent into the saliva in the oral cavityand, further, the subsequent uptake of the nicotine from the saliva inthe oral cavity into the systemic circulation of the subject.

With nicotine it is intended to include nicotine,3-(1-methyl-2-pyrrolidinyl)-pyridine, with its base form, includingsynthetic nicotine as well as nicotine extracts from tobacco plants, orparts thereof, such as the genus Nicotiana alone or in combination orpharmaceutically acceptable salts.

Preferred embodiments incorporate nicotine as

(a) the free base form;

(b) a water-soluble pharmaceutically acceptable salt, either per se oradsorbed on an adsorbent;

(c) a complex with a cation exchanger;

(d) mixtures of any of (a)-(c);

(e) an inclusion complex, such as a cyclodextrin complex, e.g.β-cyclodextrin, or nicotine in any non-covalent binding;

(f) nicotine bound to zeolites;

(g) nicotine bound to cellulose or starch microspheres; and

(h) mixtures of any of the foregoing.

Also, any other suitable pharmaceutically acceptable form may also beemployed.

As noted above, numerous nicotine salts are known, and may be used.Particular examples of suitable salts include those presented in Table1, such as preferably the tartrate, hydrogen tartrate, citrate, malate,and/or hydrochloride.

TABLE 1 Possible acids used for nicotine salt formation Acid Molarratio* of acid:nicotine Formic 2:1 Acetic 3:1 Propionic 3:1 Butyric 3:12-Methylbutyric 3:1 3-Methylbutyric 3:1 Valeric 3:1 Lauric 3:1 Palmitic3:1 Tartaric 2:1 Citric 2:1 Malic 2:1 Oxalic 2:1 Benzoic 1:1 Gentisic1:1 Gallic 1:1 Phenylacetic 3:1 Salicylic 1:1 Phthalic 1:1 Picric 2:1Sulfosalicylic 1:1 Tannic 1:5 Pectic 1:3 Alginic 1:2 Hydrochloric 2:1Chloroplatinic 1:1 Silicotungstic 1:1 Pyruvic 2:1 Glutamic 1:1 Aspartic1:1 *recommended upon production

As noted above the nicotine may be present in the chewing gum in acomplex with a cation exchanger. Suitable cation exchangers are listedbelow Table 2 and are further disclosed in U.S. Pat. No. 3,845,217,hereby incorporated by reference herein as to the description of suchcation exchangers. Preferred are nicotine cation exchangers ofpolyacrylates, such as the AMBERLITE products from Rohm & Haas in Table2.

TABLE 2 Representative cation exchangers Name Manufacturer Amberlite IRC50 Rohm & Haas Amberlite IRP 64 Rohm & Haas Amberlite IRP 64M Rohm &Haas BIO-REX 70 BIO-RAD Lab. Amberlite IR 118 Rohm & Haas Amberlite IRP69 Rohm & Haas Amberlite IRP 69M Rohm & Haas BIO-REX 40 BIO-RAD Lab.Amberlite IR 120 Rohm & Haas Dowex 50 Dow Chemical Dowex 50W DowChemical Duolite C 25 Chemical Process Co Lewatit S 100 FarbenfabrikenBayer Ionac C 240 Ionac Chem. Wofatit KP S 200 I.G. Farben WolfenAmberlyst 15 Rohm & Haas Duolite C-3 Chemical Process Duolite C-10Chemical Process Lewatit KS Farbenfabriken Bayer. Zerolit 215 ThePermutit Co. Duolite ES-62 Chemical Process BIO-REX 63 BIO-RAD Lab.Duolite ES-63 Chemical Process Duolite ES-65 Chemical Process Ohelex 100BIO-RAD Lab. Dow Chelating Resin A-1 Dow Chemical Company PuroliteC115HMR Purolite International Ltd. CM Sephadex C-25 Pharmacia FineChemicals SE Sephadex C-25 Pharmacia Fine Chemicals

A coated chewing gum according to the present invention may comprise oneor more further non-active excipients or additional active ingredients,preferably selected from the compounds listed herein.

One or more fluoride ion sources may be incorporated into the coatingcompositions as anticaries agents. Fluoride ions may be included forthis purpose. Detailed examples of such fluoride ion sources can befound in U.S. Pat. No. 6,121,315 to Nair et al., herein incorporated byreference as to the description of such fluoride ion sources.

Also useful herein are tooth desensitizing agents. Tooth desensitizingagents that may be used in the present invention include potassiumnitrate, citric acid, citric acid salts, strontium chloride, and thelike, as well as other desensitizing agents known in the art. Oneparticular embodiment includes a desensitizing agent in combination witha tooth whitening agent. The amount of desensitizing agent includedwithin the dental whitening compositions of the present invention mayvary according to the concentration of the potassium nitrates, thedesired strength and intended treatment times. Accordingly, if includedat all, the other desensitizing agents will preferably be included in anamount in a range from about 0.1% to about 10% by weight of the dentaldesensitizing composition, more preferably in a range from about 1 toabout 7% by weight of the wet film composition.

An individual enzyme or a combination of several compatible enzymes canalso be included in the chewing gum composition of the presentinvention.

Antioxidants are generally recognized as useful in compositions such asthose of the present invention. Antioxidants that may be included in thecoating compositions of the present invention include, but are notlimited to, Vitamin E, ascorbic acid, uric acid, carotenoids, Vitamin A,flavonoids and polyphenols, herbal antioxidants, melatonin,aminoindoles, lipoic acids and mixtures thereof.

It may be desirable to add pH adjusting agents, or buffers, such assodium bicarbonate, sodium phosphate, sodium hydroxide, ammoniumhydroxide, sodium stannate, citric acid, hydrochloric acid, sodiumcitrate, and combinations thereof to the core and/or to any of thecoatings. The pH adjusting agents are added in sufficient amounts so asto adjust the pH of oral cavity to a suitable value, e.g. from about 4.5to about 11, preferably from about 5.5 to about 8.5.

EXAMPLES

The following Examples are offered as illustrative of the invention andare not to be construed as limitations thereon. In the Examples andelsewhere in the description of the invention, chemical symbols andterminology have their usual and customary meanings. The term “set” isan inclusive term used to mean a single or more than one ingredient ofthe type described. In the Examples as elsewhere in this application theproportions of the components are in weight percents according to thestandard described, or if no standard is described of the total weightof the composition.

The Examples may be modified according to suitable and conventionalmanufacturing methods known in the art. The methods of the Examples maybe modified e.g. in accordance with the methods disclosed in WO02/102357, herein incorporated by reference as to the description ofmanufacturing methods.

Example 1 Nicotine-containing Chewing Gums

Chewing gums according to the present invention, preferably eachcontaining 2 mg or 4 mg nicotine calculated as the free base aremanufactured according to the below process. The number of gums beingmanufactured per batch will depend on the equipment used.

The following steps are carried out:

-   1. Chewing gum base is loaded into a pre-heated mixer and agitated    therein.-   2. A first set of flavoring agent(s), sweetener(s), pH regulating    agents and nicotine resin complex are added and mixed therein until    a homogenous distribution of the ingredients is obtained.-   3. The chewing gum mass is extruded, conditioned and rolled and    scored to form chewing gum sheets.-   4. The chewing gum sheets are conditioned and then broken into    individual chewing gum cores.-   5. A polymer-containing coating solution, e.g. comprising HPMC, is    prepared. A second set of sweetener(s) and flavoring agent(s) are    added to the solution.-   6. The chewing gum cores are loaded into coating pans where they are    sprayed with the coating solution from Step 5.-   7. A hard coating solution comprising a third set of sweetener(s)    and, optionally, a third set of flavoring agent(s) is prepared.-   8. The coated gum cores are again loaded into coating pans. The    coating solution from Step 7 is sprayed in cycles onto the coated    gum cores.-   9. Optionally wax is sprayed onto the coated gum cores in order to    provide a glossy finish.

In Step 6 the coating solution is applied using a spray coater. Forexample, gum cores are film coated in a controlled atmosphere inside aperforated rotating drum. Angled baffles are fitted into the drum andair flow inside the drum provides means of mixing the gum cores bed. Asa result, the gum cores are lifted and turned from the sides into thecenter of the drum, exposing each gum core surface to an even amount ofdeposited/sprayed film forming agent to produce a coating. The liquidspray coating is then dried onto the gum core by air drawn through thetablet bed from an inlet fan. The air flow is regulated for temperatureand volume to provide controlled drying and extracting rates, and at thesame time, maintaining the drum pressure slightly negative relative tothe room in order to provide a completely isolated process atmospherefor the operator.

Suitable coating equipment may include spray guns, coating pan,polishing pans, solution tanks, blenders and mixers, homogenizers,mills, peristaltic pumps, fans, steam jackets, exhaust and heatingpipes, scales and filters. In particular, any commercial spray coatermay be used to apply the coating. Examples of useful coaters are VectorHigh Coaters manufactured by Vector Corporation and Accela-Coatmanufactured by Thomas Engineering. Equipment variables which oneskilled in the art can manipulate to provide a coating based on HPMC orHPC, include inlet temperature, outlet temperature, air flow, speed ofrotation of the coating pan, and the rate at which the coatingformulation is pumped to the coater. It is important that the inlet andoutlet temperatures be controlled so that they are high enough toefficiently dry the coating to prevent the tumbling action of thealready-coated tablets from damaging the newly-applied coating beforemore coating is applied to the same tablets.

A chewing gum comprising 2 mg nicotine being manufactured in accordancewith the above process may have the following composition:

the gum core: 314 mg xylitol, 20 mg sodium carbonate anhydrous, 10 mgsodium hydrogen carbonate, 1 mg magnesium oxide light, 2 mg acesulfamepotassium, 11 mg nicotine resin complex 20%, 560 mg chewing gum base, 2mg levomenthol and 30 mg peppermint oil;

the polymer coating: 11.5 mg Methocel K3 Prem LV (HPMC 2208, 3 cps), 5mg sucralose NF, 0.5 mg Polysorbate 80 NF/EP, 10 mg cinnamon flavor and3 mg Indian fire flavor;

the hard coating: 270 mg xylitol, 6 mg acacia spray-dried, 5 mg titaniumdioxide, 6.15 mg cinnamon flavor, 1.85 mg Indian fire flavor and 1 mgcarnauba wax.

Example 2 Alternative Nicotine-containing Chewing Gums

Several modifications to the process described in Example 1 and theproduct resulting therefrom are possible. For example:

(a) Instead of HPMC, one can use hydroxy propyl cellulose (HPC), such asKlucel EF from Aqualon.

(b) A plasticizer may be mixed into the polymer film in order to improveflexibility of the film. Examples of suitable plasticizers include, butare not limited to, citric acid alkyl esters, glycerol esters such asglycerol monooleate and glycerol monostearate, phthalic acid alkylesters, sebacic acid alkyl esters, sucrose esters, sorbitan esters,acetylated monoglycerides, glycerols, fatty acid esters, glycols,propylene glycol, and polyethylene glycols 200 to 12,000 and mixturesthereof. Specific plasticizers include, but are not limited to, lauricacid, sucrose, sorbitol, triethyl citrate, acetyl triethyl citrate,triacetin (glyceryl triacetate), poloxamers, alkyl aryl phosphates,diethyl phthalate, mono- and di-glycerides of edible fats or oilssupplied by Lonza Inc., tributyl citrate, dibutyl phthalate, dibutylsebacate, polysorbate, Carbowax® series of polyethylene glycols (UnionCarbide Corporation) and mixtures thereof. Preferred plasticizersinclude polyethylene glycol 400 (PEG 400) in amounts ranging from about0 to about 10% by weight, preferably about 0 to about 3% by weight.

(c) Particular embodiments include those where the level of polymercoating applied to the gum cores is preferably between about 0.5% andabout 20% by weight of the uncoated gum cores, more preferably betweenabout 2% and about 3.5% by weight of the uncoated gum cores. This levelof coating provides an elegant and serviceable coating. To apply aheavier coating to the gum cores would not be economical, and it mightadversely affect active release or other properties. Too light a coatingwould not provide optimal properties normally expected from a coating.

(d) In general, an effective amount of auxiliary sweetener is utilizedto provide the level of sweetness desired for a particular composition,and this amount will vary with the sweetener selected. This amount willnormally be from about 0.01% to about 30% by weight of the polymer filmcoating when using sucralose and, most preferably, in amount of fromabout 10% to about 20% by weight. These amounts may be used to achieve adesired level of sweetness independent from the flavor level achievedfrom any optional flavor oils used.

(e) The polymer used in the polymer coating is preferably water-solubleand is present therein in an amount up to about 99% by weight,preferably up to about 80% by weight, more preferably up to about 50% byweight, and most preferably up to about 40% by weight of the polymercoating.

(f) In Step 7 may be added non-ionic emulsifiers such as mono- anddiglycerides of fatty acids, ethylene glycol fatty acid esters,propylene glycol fatty acid esters, glycerol monostearate, andpolyoxyethylene sorbitol esters. Specific examples are Atmos 300 andPolysorbate 80. Said emulsifiers can be added in amounts ranging fromabout 0.5% to about 15% by weight, preferably from about 1% to about 5%by weight of the polymer film coating.

(g) The amount of flavoring employed is normally a matter of preferencesubject to such factors as flavor type, individual flavor, and strengthdesired. Thus, the amount may be varied in order to obtain the resultdesired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. In general, in the inner polymer film amounts of fromabout 0.1% to about 60% by weight are useable with amounts of from about2% to about 50% by weight being preferred and amounts from about 30% toabout 50% by weight being more preferred.

(h) Further additives as stated above may be incorporated in the chewinggums.

A typical inner polymer film coating comprises the hydroxypropylmethylcellulose Methocel K3, the surfactant Polysorbate 80, the sweetenerSucralose and flavor. The inner polymer film coating may additionallycomprise the hydroxypropyl cellulose Klucel EF. A typical outer hardcoating comprises the sweetener Xylitol, the film former Gum Arabic, thecolorant titanium dioxide, flavors and Carnauba Wax.

Example 3 Chewing Gums Comprising other APIs than Nicotine

Chewing gums according to the present invention comprising API's otherthan nicotine may be manufactured according to Example 1 or Example 2.

Example 3A Chewing Gums Comprising Dextromethorphan

A dextromethorphan-containing chewing gum, eg having a gum corecomprising 10 mg of the AIP dextromethorphan, may have an inner polymerfilm comprising the hydroxy propyl methyl cellulose Methocel K3, thesurfactant Polysorbate 80, the sweetener Sucralose, the AIPdextromethorphan and Mint Flavor. The outer hard coating may comprisethe sweetener Xylitol, the film former Gum Arabic, the colorant TitaniumDioxide, Mint Flavor and Carnauba Wax.

Example 3B Chewing Gums for Oral Care

A chewing gum for oral care may have an inner polymer film comprisingthe hydroxy propyl methyl cellulose Methocel K3; the surfactantPolysorbate 80; the sweetener Sucralose; the AIP's menthol, Thymol,Eucalyptol and methyl salicylate; and a flavoring such as peppermintflavor. The outer hard coating may comprise the sweetener Xylitol, thefilm former Gum Arabic, the colorant titanium dioxide, peppermint flavorand Carnauba Wax.

What is claimed is:
 1. A chewing gum comprising: (a) a core comprisingchewing gum base, nicotine in any form, a first flavoring agent, a firstsweetener and at least one pH regulating agent; (b) an inner polymercoating on the core, a second flavoring agent in an amount from 30% to50% by weight of said inner polymer coating and a second sweetenerwherein the amount of inner polymer coating is about 0.5% to about 20%by weight of the core; and (c) an outer hard coating on the innerpolymer coating whereby the flavor perceived upon chewing of the chewinggum predominantly is the flavor provided by said at least one secondflavoring agent.
 2. The chewing gum according to claim 1, wherein saidinner polymer coating comprises water soluble natural or syntheticpolymer selected from the group consisting of hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodiumalginate, polyethylene glycol, pullulan, tragacanth gum, guar gum,acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer,carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylatedhigh amylose starch, dextrin, pectin, chitin, chitosan, gelatin, zein,gluten, soy protein isolate, whey protein-isolate, casein and mixturesthereof.
 3. The chewing gum according to claim 1, wherein said innerpolymer coating comprises a water-insoluble polymer selected from thegroup consisting of hydrogenated vegetable oils, hydrogenated castoroil, polyvinyl chloride, shellac, polyure-thane, cellulose derivatives,gum rosins, wood rosens, waxes, acrylate and methacrylate polymers,copolymers of acrylic and methacrylic acid esters and mixtures thereof.4. The chewing gum according to claim 2, wherein said inner polymercoating further comprises a plasticizer.
 5. The chewing gum according toclaim 1, wherein said inner polymer film coating and said outer hardcoating are devoid of any active pharmaceutical ingredient.
 6. Thechewing gum according to claim 1, wherein said inner polymer filmcoating further comprises one or more ingredients selected from thegroup consisting of: fluoride ion sources, tooth desensitizing agents,enzymes, antioxidants, pH adjusting agents, and mixtures of theforegoing.
 7. The chewing gum according to claim 1, wherein said firstflavoring agent is mint and said second flavoring agent is selected fromthe group consisting of citrus, cinnamon, berry or mixed fruit.
 8. Thechewing gum according to claim 1, wherein said inner polymer coatingfurther comprises a plasticizer.
 9. The chewing gum according to claim8, wherein said plasticizer comprises polysorbate.
 10. A chewing gumcomprising: (a) a core comprising chewing gum base, nicotine in any formand a first flavoring agent; (b) an inner polymer coating on the coreand a second flavoring agent in an amount from 30% to 50% by weight ofsaid inner polymer coating wherein the amount of inner polymer coatingis about 0.5% to about 20% by weight of the core; and (c) an outer hardcoating on the inner polymer coating whereby the flavor perceived uponchewing of the chewing gum predominantly is the flavor provided by saidat least one second flavoring agent.
 11. The chewing gum according toclaim 10, wherein said core further comprises a sweetener.
 12. Thechewing gum according to claim 10, wherein said inner polymer coatingfurther comprises a sweetener.
 13. The chewing gum according to claim10, wherein said outer polymer coating further comprises a sweetener.14. The chewing gum according to claim 10, wherein said inner polymerfilm coating and said outer hard coating are devoid of any activepharmaceutical ingredient.
 15. The chewing gum according to claim 10,wherein said inner polymer film coating further comprises one or moreingredients selected from the group consisting of: fluoride ion sources,tooth desensitizing agents, enzymes, antioxidants, pH adjusting agents,and mixtures of the foregoing.
 16. The chewing gum according to claim10, wherein said first flavoring agent is mint and said second flavoringagent is selected from the group consisting of citrus, cinnamon, berryor mixed fruit.
 17. The chewing gum according to claim 10, wherein saidinner polymer coating further comprises a plasticizer.
 18. The chewinggum according to claim 17, wherein said plasticizer comprisespolysorbate.
 19. The chewing gum according to claim 10, wherein saidinner polymer coating comprises water soluble natural or syntheticpolymer selected from the group consisting of hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodiumalginate, polyethylene glycol, pullulan, tragacanth gum, guar gum,acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer,carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylatedhigh amylose starch, dextrin, pectin, chitin, chitosan, gelatin, zein,gluten, soy protein isolate, whey protein-isolate, casein and mixturesthereof.
 20. The chewing gum according to claim 4, wherein saidplasticizer comprises polysorbate.